1. Field of the Invention
The invention relates to compounds which act as prodrugs for the anti-cancer agent paclitaxel and which are substantially water-soluble, as well as pharmaceutical compositions containing such prodrugs and methods of treatment using such compositions.
2. Description of the Prior Art
Paclitaxel is a natural diterpene product isolated from the Pacific yew tree (Taxus brevifolia). It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. (J. Am. Chem. Soc., 93:2325, 1971), who characterized its structure by chemical and X-ray crystallographic methods.
Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583,1991; McGuire et al., Ann. Intern. Med., 111:273, 1989). It is effective for chemotherapy for several types of neoplasms including breast (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991) and has been approved for treatment of breast cancer as well. It is a potential candidate for treatment of neoplasms in the skin (Einzig et al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et al. Sem. Oncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et al., Nature, 368:750, 1994), lung cancer and malaria.
Paclitaxel is only slightly soluble in water and this has created significant problems in developing suitable injectable and infusion formulations useful for anticancer chemotherapy. Some formulations of paclitaxel for IV infusion have been developed utilizing CREMOPHOR EL.TM. (polyethoxylated castor oil) as the drug carrier because of paclitaxel's aqueous insolubility. For example, paclitaxel used in clinical testing under the aegis of the NCI has been formulated in 50% CREMOPHOR EL.TM. and 50% dehydrated alcohol. CREMOPHOR EL.TM., however, when administered intravenously, is itself toxic and produces vasodilation, labored breathing, lethargy, hypotension and death in dogs. It is also believed to be responsible for the allergic-type reactions observed during paclitaxel administration.
In an attempt to increase paclitaxel's solubility and to develop safer clinical formulations, studies have been directed to synthesizing paclitaxel analogs where the 2' and/or 7-position is derivatized with groups that would enhance water solubility. These efforts have yielded prodrug compounds that are more water-soluble than the parent compound and that display the cytotoxic properties upon activation. One important group of such prodrugs includes the 2'-onium salts of paclitaxel and docetaxel, particularly the 2'-methylpyridinium acetate (2'-MPA) salts (see Nicolaou et al., Angew. Chim. Int. Engl., 33:1583-1587, 1994).
We have recently discovered that the paclitaxel onium salt 2'-MPA paclitaxel is difficult to prepare in substantially pure form and yields of the pure salt by the syntheses proposed in the scientific and patent literature are very low. This is primarily because these syntheses yield initially no more than 65-70% of the salt in mixture with paclitaxel (and small amounts of other impurities). After being separated from paclitaxel by HPLC in a solvent containing excess acetate ion (e.g., ammonium acetate), the salt decomposes rapidly, upon concentration of the HPLC effluent, to paclitaxel and very little of the 2'-MPA can be isolated. The poor yield of pure prodrug onium salt is a major inhibition to development of such a product as a commercially viable pharmaceutical because the paclitaxel starting material is extremely expensive and it is not feasible to use substantial quantities of paclitaxel to produce minute amounts of pure or substantially pure prodrug end product.
Improved prodrugs of paclitaxel which are both highly soluble in water, stable and relatively simple to prepare in high yield and purity are required.